The regulation of blood pressure during exercise is of paramount importance to ensure adequate perfusion of vital organs and exercising skeletal muscle. It has been argued that because the vast majority of cardiac output during exercise is directed toward active skeletal muscle, vasoconstriction in exercising skeletal muscle is of primary importance in maintaining blood pressure. Indeed, previous publications by the applicant demonstrated substantial alpha adrenergic receptor mediated vasoconstriction in exercising skeletal muscle even at heavy workloads. Stimulation of non-adrenergic receptors in vascular smooth muscle, such as purinergic (P2X), neuropeptide Y (NPY Y1), and endothelin (ETA) receptors can also produce vasoconstriction in the vasculature of resting skeletal muscle, but the contribution of these receptors to tonic vasoconstriction in exercising skeletal muscle remains largely unknown. Preliminary data in this application clearly demonstrate the potential for P2X and NPY Y1 receptor mediated vasoconstriction in exercising skeletal muscle. Despite the existence of sympathetic vasoconstriction in active skeletal muscle, previous work by the applicant demonstrated that exercise produces an attenuation of alpha adrenergic receptor responsiveness in the vasculature of skeletal muscle. It remains to be determined whether non-adrenergic receptors in vascular smooth muscle exhibit a similarly reduced responsiveness from rest to exercise although pilot studies described in this application provide an intriguing suggestion that P2X and NPY Y1 receptor responsiveness in skeletal muscle is also attenuated during exercise. The overall hypothesis underlying this proposal is that non-adrenergic receptors contribute to vasoconstriction in exercising skeletal muscle. Two specific aims are proposed: 1. To determine the contribution of non-adrenergic receptors to vasoconstriction in exercising skeletal muscle. 2. To examine non-adrenergic receptor responsiveness in the vasculature of skeletal muscle at rest and exercise. A major strength of the proposed studies is the ability to study basic physiological mechanisms in conscious, exercising animals. A unique aspect of the experimental protocols is the ability to deliver agonists and antagonists to a discrete vascular bed without altering arterial pressure or blood flow in other vascular beds. The proposed studies will provide valuable new information regarding the physiological mechanisms by which blood flow to active skeletal muscle is regulated during dynamic exercise. This is an issue of fundamental importance that may have important implications for individuals with peripheral vascular disease.